NMDA (N-methyl-D-aspartate) is the defining agonist of a subclass of ionotropic glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that depolarizes the cell and increases the concentration of Ca2+ in the cell, which is a secondary messenger in various signaling pathways. NMDA receptors play a role in physiological process such as memory and depression. See e.g., Nicholls et al., Neuron, 2008, 58(1):104-17.
Agents that modulate NMDA receptors are known for a variety of therapeutic applications. For example, memantine is used to treat Alzheimer's disease and dementia with Lewy bodies. Amantadine is an anti-Parkinsonian drug. Ketamine is used for the induction and maintenance of general anesthesia, and has recently been shown to be effective in clinical trials against treatment-resistant depression. Common side effects of NMDA modulators are sedation and hallucinations. Thus, there is a need to identify improved agents.
Mosley et al. reported quinazolin-4-one derivatives as a novel class of noncompetitive NR2C/D subunit-selective NMDA receptor antagonists. See J Med Chem, 2010, 53(15), 5476-5490. Mullasseril et al. reported on a NR2C/D-selective class of NMDA receptor potentiators. See Nat Commun. 2010, 1:90. See also WO 2010/088414, WO 2010/114636, WO 2010/081783, WO 2012/098172, WO 2004/000227, WO 2008/120725, and CN 102603717.